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Deciphering the origins of molecular toxicity for combretastatin A4 and its glycoconjugates: Interactions with major drug transporters and their safety profiles in vitro and in vivo

Abstract

Cellular uptake and transport mechanism directly correlate with drug-like profiles of a lead compound. To decipher the molecular origin of the toxicity of combretastatin A4 (CA4), an important microtubule targeting agent, we investigated the interactions between CA4 and six key drug transporters, namely hOAT1, hOAT3, hOCT1, hOCT2, hOATP1B3, and hOATP2B1. Three combretastatin-based glycoconjugates, namely Glu-CA4, Man-CA4, and Gal-CA4 with glucose, mannose, and galactose respectively, were synthesized and their in vitro and in vivo biological characteristics were evaluated. CA4 exhibited significant inhibition against hOAT3 and hOATP2B1, moderate inhibition of hOAT1 and hOCT2, with weak inhibitory effects on hOCT1 and hOATP1B3. Compared to CA4, the inhibitory activities of Glu-CA4 on the six transporters were minimal. The glycoconjugates were found to have a superior safety profile with their maximum tolerated dose (MTD) values exhibiting a 16~34-fold increase compared to CA4. Given the drawbacks of CA4, the enhanced solubility and safety profiles of CA4 glycoconjugates auger well for further investigation into these intriguing candidates’ in vivo efficacy.

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Publication details

The article was received on 11 May 2017, accepted on 03 Jun 2017 and first published on 12 Jun 2017


Article type: Research Article
DOI: 10.1039/C7MD00246G
Citation: Med. Chem. Commun., 2017, Accepted Manuscript
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    Deciphering the origins of molecular toxicity for combretastatin A4 and its glycoconjugates: Interactions with major drug transporters and their safety profiles in vitro and in vivo

    Z. Huang, G. Li, X. Wang, H. Xu, Y. Zhang and Q. Gao, Med. Chem. Commun., 2017, Accepted Manuscript , DOI: 10.1039/C7MD00246G

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